Molecular modeling of D151Y and M391T mutations in the LDL receptor.
The low-density lipoprotein receptor (LDLR) is a key regulator of cholesterol homeostasis, and defects in the function of LDLR result in familial hypercholesterolemia (FH). In the present study, we performed structural analyses of two novel LDLR mutations, D151Y and M391T. Both mutations occurred in conserved residues of LDLR. The D151Y mutation, in the ligand binding domain, caused an elimination of a hydrogen bond in the calcium binding site, higher solvent accessibility and a loss of negative charge in the Y151 residue. On the other hand, the M391T mutation, in the beta-propeller of the epidermal growth factor (EGF) precursor homology domain, caused an additional hydrogen bond to form, higher solvent accessibility and a distortion of the beta-strand. These data suggest that the irregular structures of the mutated LDLRs are likely to cause the functional defect that contributes to the pathology of FH.
Jeenduang
Nutjaree
N
Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, 2 Pran Nok Road, Bangkok 10700, Thailand.
Promptmas
Chamras
C
Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, 2 Pran Nok Road, Bangkok 10700, Thailand.
Pongrapeeporn
Klai-Upsorn S
KS
Heart Genetics Company, Bangkok 10400, Thailand.
Porntadavity
Sureerut
S
Department of Clinical Chemistry, Faculty of Medical Technology, Mahidol University, 2 Pran Nok Road, Bangkok 10700, Thailand. Electronic address: mtspy@mahidol.ac.th.
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D000818:Animals; D003198:Computer Simulation; D017124:Conserved Sequence; D004252:DNA Mutational Analysis; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation; D011487:Protein Conformation; D051381:Rats; D011973:Receptors, LDL / Q000737:chemistry* / Q000235:genetics*; D020539:Sequence Analysis, Protein
D011973:Receptors, LDL